Application to the mucosa as a method of drug therapy has been recognized as a useful means of medication for such reasons as (1) it permits direct application to the affected area for diseases of local areas such as nasal mucosa, oral mucosa, and vaginal mucosa, (2) its immediate effects for systemic diseases can be expected as in the case of a nasal spray to the nasal mucosa and a suppository to the rectal mucosa, and (3) its application is easy compared to injection, as represented by an oral drug targeted at the intestinal mucosa, and the like. For example, pharmaceutical preparations for application to the mucosa have already been commercially available due to reason (1) in the case of nasal sprays for treatment of allergic rhinitis, and due to reason (2) in the case of suppositories to alleviate pain.
As pharmaceutical preparations for local mucus diseases, Saunders et al., (WO 92-14473), for example, provides a suspension preparation containing Tipredane as the main drug as the pharmaceutical preparation for treatment of allergic rhinitis. Also, Helzner (WO 97-01337) provides a pharmaceutical preparation comprising an antihistamic drug, a steroid and water as the pharmaceutical preparation for treatment of allergic rhinitis. As the pharmaceutical preparation for local mucus diseases, furthermore, Kim et al., (WO 98-00178) provides a suspension preparation having a thixotropic property as the pharmaceutical preparation for application to the nasal mucosa. Suzuki et al. (Japanese Examined Patent Publication (Kokoku) No. 60 (1985)-34925) also provides a sustained release pharmaceutical preparation for administration to the nasal cavity that permits the efficient supply of the drug at a concentration sufficient to obtain a therapeutic effect.
As the pharmaceutical preparations for systemic diseases, several methods have been provided that enhance the absorption of drugs through the mucosa. Nagata et al. (Japanese Unexamined Patent Publication (Kokai) No. 63 (1988)-303931), for example, provides a method of applying to the nasal cavity a growth hormone-releasing factor at the liquid form having an osmotic pressure ratio of 1 (an osmotic pressure of 290 mOsm) or lower as a method for enabling quick and efficient absorption of the a growth hormone-releasing factor through the nasal mucosa to the blood circulation. Furthermore, Ohwaki et al. (Japanese Unexamined Patent Publication (Kokai) No. 60 (1985)-123426) provides a method of applying to the nasal cavity a solution of secretin having an osmotic pressure ratio of 1 to 5 (an osmotic pressure of 290-1450 mOsm) and a pH of 2 to 5 as a method for enabling quick absorption of secretin through the nasal mucosa to blood circulation. Furthermore, Awatsu et al. (Pharm. Res. Vol. 10, No. 9, 1372-1377, 1993) provides a method of applying to the nasal mucosa a pharmaceutical solution to which polyoxyethylene 9-laurylether was added as an absorption enhancer as a method for enabling efficient absorption of a granulocyte colony-stimulating factor through the nasal mucosa to blood circulation.
However, when these pharmaceutical preparations are given to the mucosa, liquid-dripping can occur, or the pharmaceutical preparations are quickly excreted to the outside of the mucus tissue due to a mucociliary clearance function etc. before being adequately transported or permeated to the mucosa tissue. Because of this, the transport of an adequate amount of drug into the blood cannot be effected when systemic administration through transport to the blood circulation is attempted. Furthermore, the method of using an absorption enhancer is yet to be realized because the absorption enhancer has the problem of irritating the nasal mucosa. On the other hand, when local administration is attempted through retention of the drug in the mucosa tissue, an adequate amount of the drug cannot be retained at the tissue. In addition, even if the problem of retentivity has been solved, permeation into the mucosa tissue is not adequate.
Thus, it is strongly desired to develop a pharmaceutical preparation for application to the mucosa, that allows the transport of an adequate amount of the drug through the mucosa to the blood circulation after the application to the mucosa. Alternatively, it is strongly desired to develop a pharmaceutical preparation for application to the mucosa that enables the transport to and retention in the mucosa tissue of an adequate amount of the drug when applied to the mucosa.